This is a proposal to continue funding for a Program Project that seeks to elucidate the molecular mechanisms involved in the induction and maintenance of immune tolerance and the counter-regulation of ongoing immune responses. The three investigators each conduct research based on the premise that immune regulation is complex, and the inherent responsiveness of immune cells and interactions with their anatomical microenvironments play pivotal roles in determining responses to self- and pathogen-associated antigens. In keeping with the overall theme of the Program Project, the projects proposed in this renewal examine the mechanistic aspects of tolerance and immune regulation in the context of the interactive nature of the immune system. Accomplishments by the individual investigators during the last funding period include the design and characterization of experimental models that are now amenable to meaningful mechanistic analyses. These models provide novel methodologies and insights that continue to bridge the three projects, thereby facilitating synergy and increasing the scientific scope of the individual laboratories. Dr. Chris Hunter has been incorporated as a new member of the Program Project. Dr. Hunter will study how various cytokines and signal transducers activate and properly limit peripheral T cell responses to pathogens. An administrative core will provide budget oversight, support for manuscript preparation and progress reports, and logistical support for investigator meetings and arrangements for the collaborators and outside speakers. Continued integration of the three laboratories will enhance the quality of the science and the overall productivity such that the Project as a whole will be greater than the sum of the individual laboratories. RELEVANCE: Proper immune responses function to control pathogenic infections. It is equally important to limit immunological responses properly, because failure to do so may cause chronic inflammation or autoimmune diseases. Thus, understanding the molecular and cellular pathways that appropriately regulate immune responses will provide the foundation for novel intervention strategies against various autoimmune diseases. PROJECT 1: T cell-intrinsic and extrinsic factors controlling immune responses (Yongwon Choi, Project Leader) PROJECT 1 DESCRIPTION (provided by applicant): T cell immune responses are governed by multiple factors expressed on the cell surface, including antigen receptors, costimulatory proteins, and inhibitory molecules. In addition, interactions with antigen-presenting cells of a certain status (e.g., quiescent or activated dendritic cells) mediate the activities of T cells. The major goal of this proposal is to understand how T cell responses are regulated by mechanisms that are intrinsic or extrinsic to the cells themselves. During the current funding period, we have shown that TRAF6 acts as a T cell receptor-dependent negative regulator of T cell responses. We have demonstrated that this protein regulates the induction of T cell anergy and T helper cell differentiation. These results show that TRAF6 has previously unrecognized, cell-intrinsic functions in T lymphocytes to govern multiple aspects of T cell fate. Therefore, we propose to extend our studies of the roles of TRAF6 in T cells by pursuing the following aims: (i) determine the molecular mechanisms leading to the impaired induction of T cell anergy observed in TRAF6-deficient CD4+ T cells;(ii) determine the effects of T cell-specific TRAF6 deficiency on T cell differentiation;and (iii) examine how TRAF6-deficient dendritic cells affect T cell immune responses in vivo. We believe the third goal is a logical extension of this work because TRAF6 is a key signal transducer for CD40 and IL-1/Toll-like receptors. The proposed studies should help to elucidate how T cell responses are controlled at the molecular and cellular level. Such studies will provide the basis for novel therapeutic strategies for various autoimmune diseases and new methods to control T cell immune responses during chronic inflammation. RELEVANCE: Proper immune responses are necessary to control pathogenic infections. It is equally important to limit immunological responses properly so that they do not cause chronic inflammation or autoimmune diseases. Thus, understanding molecular and cellular pathways that properly control immune responses will provide the foundation for novel intervention strategies to treat various chronic inflammatory diseases.